HIV replication is associated to inflammasomes activation, IL-1ß, IL-18 and caspase-1 expression in GALT and peripheral blood.

BACKGROUND: Human immunodeficiency virus (HIV) promotes an inflammatory process, leading to the progressive loss of the functional capacity of the immune system. The HIV infection induces alterations in several tissues, but mainly in the gut-associated lymphoid tissue (GALT). However, the degree of GALT deterioration varies among infected individuals. In fact, it has been shown that HIV-controllers, who spontaneously control viral replication, exhibit a lower inflammatory response, and a relative normal frequency and function of most of the immune cells. Inflammasomes are molecular complexes involved in the inflammatory response, being NLRP1, NLRP3, NLRC4, AIM2 and Pyrin inflammasomes, the best characterized so far. These complexes regulate the maturation of cytokines of the IL-1 family, including IL-1ß and IL-18. These cytokines have been associated with immune activation and expansion of HIV target cells, promoting viral replication. Interesting, some reports indicate that HIV induces the activation of the NLRP3 inflammasome, but the role of this, and other inflammasomes during HIV infection, especially in GALT, remains unclear. OBJECTIVE: To compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers. METHODS: GALT biopsies and peripheral blood mononuclear cells (PBMCs) from 15 HIV-controllers and 15 HIV-progressors were obtained. The relative expression of the following inflammasome components were evaluated by RT-PCR: NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1ß and IL-18. In addition, plasma concentration of IL-18 was evaluated as an indicator of baseline proinflammatory status. Finally, in supernatants of PBMCs in vitro stimulated with inflammasome agonists, the concentrations of IL-1ß and IL-18 were quantified by ELISA. RESULTS: HIV-progressors exhibited higher expression of IL-1ß, IL-18 and caspase-1 genes in GALT and PBMCs compared with HIV-controllers. In addition, HIV-progressors had also increased expression of ASC in PBMCs. When plasma levels were evaluated, IL-18 was increased in HIV-progressors. Interesting, these patients also showed an increased production of IL-1ß in supernatants of PBMCs stimulated in vitro with the agonists of AIM2, NLRP1 and NLRC4 inflammasomes. Finally, the expression of caspase-1, NLRP1, IL-1ß and IL-18 in GALT or peripheral blood was correlated with CD4+ T-cell count and viral load. CONCLUSION: Our results suggest that during HIV-infection, the required signals to induce the expression of different components of the inflammasomes are produced, both in GALT and in periphery. The activation of these molecular complexes could increase the number of target cells, favoring HIV replication and cell death, promoting the disease progression.

The Spontaneous Control of HIV Replication is Characterized by Decreased Pathological Changes in the Gut-associated Lymphoid Tissue.

BACKGROUND: HIV infection induces alterations in the gut-associated lymphoid tissue (GALT) that constitutes the most important site for viral replication due to the extensive presence of effector memory T-cells. In the case of HIV-controllers, several studies have reported fewer peripheral alterations and conserved immune responses that correlate with viral control; however, the histopathological characterization of GALT in those patients is still missing. In this study, we evaluated pathological alterations in GALT, trying to associate them with clinical parameters of HIV infected patients with or without evidence of viral control. METHODS: This study included eight HIV-controllers (antiretroviral treatment-naïve patients, with viral loads below 2.000 copies/mL for at least 1 year); 14 Noncontrollers (antiretroviral treatmentnaïve patients, with viral loads > 2.000 copies/mL and CD4+ T cells count > 250 cells/µL), and 12 uninfected donors. Biopsy fragments were obtained by rectosigmoidoscopy and stained with hematoxylin and eosin, silver methenamine, Ziehl Neelsen, and modified Ziehl Neelsen. RESULTS: Histopathological findings in HIV-controllers were similar to those observed in the uninfected group. In contrast, noncontrollers exhibited several alterations including condyloma acuminate, squamous metaplasia and acute colitis. These alterations were associated with disease progression. CONCLUSION: HIV-controllers exhibit lower pathological alterations in the gut tissue, associated with higher CD4 T cell count, and lower viral load.

High Expression of Antiviral Proteins in Mucosa from Individuals Exhibiting Resistance to Human Immunodeficiency Virus.

BACKGROUND: Several soluble factors have been reported to have the capacity of inhibiting HIV replication at different steps of the virus life cycle, without eliminating infected cells and through enhancement of specific cellular mechanisms. Yet, it is unclear if these antiviral factors play a role in the protection from HIV infection or in the control of viral replication. Here we evaluated two cohorts: i) one of 58 HIV-exposed seronegative individuals (HESNs) who were compared with 59 healthy controls (HCs), and ii) another of 13 HIV-controllers who were compared with 20 HIV-progressors. Peripheral blood, oral and genital mucosa and gut-associated lymphoid tissue (GALT) samples were obtained to analyze the mRNA expression of ELAFIN, APOBEC3G, SAMHD1, TRIM5α, RNase 7 and SerpinA1 using real-time PCR. RESULTS: HESNs exhibited higher expression of all antiviral factors in peripheral blood mononuclear cells (PBMCs), oral or genital mucosa when compared with HCs. Furthermore, HIV-controllers exhibited higher levels of SerpinA1 in GALT. CONCLUSIONS: These findings suggest that the activity of these factors is compartmentalized and that these proteins have a predominant role depending on the tissue to avoid the infection, reduce the viral load and modulate the susceptibility to HIV infection.